This invention is a method for the preparation of hydrophobic polymeric microparticles which are useful for protein drug delivery, and the microparticles prepared thereby.
Microparticles prepared from synthetic polymers are currently a popular means to deliver drugs or other substances in a controlled fashion because of the chemist's ability to tailor the polymer properties to satisfy particular needs, such as degradability, swelling, permeability, temperature and pH sensitivity. Synthetic polymers must be selected that are hydrophobic so that they retain their integrity for a suitable period of time when placed in an aqueous environment, such as the body, and stable enough to be stored for an extended period before use.
A number of polymers have been used as a matrix material for delivery devices, including polyanhydrides, polyesters, polyamides, polyurethanes, polyorthoesters, polyacrylonitriles, and polyphosphazenes. Examples of synthetic polymers used for encapsulation of bioactive substances are described in European Patent Application No. 377 477.
Hydrophobic polymeric delivery devices are currently prepared in a variety of ways. A number of processes involve the use of heat. One example is the melt fabrication technique, that includes the steps of melting a polymer, mixing the melted polymer with the substance to be delivered, and then solidifying the loaded polymer by cooling. Melt fabrication processes can only be used with polymers that have a melting point that is below the temperature at which the substance to be delivered and polymer degrade or become reactive. Microparticle fabrication techniques that involve heat are not suitable for the loading of sensitive biological materials, such as proteins, bacteria, cells, including human cells, and liposomes, which are destroyed or inactivated under these conditions.
Microencapsulation has also been accomplished by spray-drying, wherein aqueous latexes of polymers or organic solutions of polymers are sprayed in a stream of hot air, and dried simultaneously. The water or other solvent is eliminated from the latex on exposure to the hot air, that is typically at a temperature of up to 140.degree. C. This technique cannot be used with soft polymer latexes which have a glass transition temperature near room temperature.
Alternatively, the device can be prepared by solvent casting (referred to as the solution evaporation or phase separation technique), wherein the polymer is dissolved in a solvent, and the substance to be delivered dissolved or dispersed in the polymer solution. The solvent is then evaporated or otherwise separated, leaving the substance in the polymeric matrix. For example, the '477 European Patent Application discloses a process for the preparation of microcapsules wherein the bioactive substance to be delivered is initially dispersed in an organic solution of polymer, and a second "hardening" organic liquid added to force phase separation of the polymer with encapsulated bioactive substance from the solution. The microcapsules are then collected, washed and dried.
Solvent casting requires that the polymer be soluble in organic solvents, and is limited to the preparation of microparticles loaded with materials that are not sensitive to organic solvents. Organic solvents often adversely affect biologically active materials. For example, sensitive proteins, including antigens and enzymes, can be denatured by organic solvents. Beneficial bacteria, including genetically engineered bacteria, and cells, including human cells, can be killed by organic solvents, and liposomal structures can be broken down by organic solvents.
Polyelectrolytes can be used for the encapsulation of biologically-labile materials without the use of heat or organic solvents. U.S. Pat. No. 5,149,543 describes a process wherein water-soluble polyelectrolytes are crosslinked with multivalent ions of opposite charge to form a gel capable of encapsulating biological material. This method is limited to polymers containing ionic groups and requires a microcapsule stabilization stage due to the sensitivity of ionotropic gels to ionic strength and pH changes.
In light of the strong need to deliver sensitive biological materials, such as proteins, bacteria, cells, including human cells, and liposomes, in a controlled fashion to a patient, it would be desirable to have a process for the encapsulation of these materials that does not require harsh conditions that can adversely affect the material, such as elevated temperature, or the use of organic solvents. It would also be desirable to have a process for the encapsulation of sensitive biological materials that does not require a stabilization step.
It is therefore an object of the present invention to provide a process for the preparation of microparticles that does not require the use of elevated temperatures or organic solvents.
It is another object of the present invention to provide a process for the preparation of microparticles of sensitive biological materials that does not require a stabilization step.
It is another object to provide microparticles with incorporated substances that are not prepared under harsh conditions that adversely affect the substance.